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Anticancer efficacy is driven not only by dose but also by frequency and duration of treatment. We describe a multiscale model combining cell cycle, cellular heterogeneity of B‐cell lymphoma 2 family proteins, and pharmacology of AZD5991, a potent small‐molecule inhibitor of myeloid cell leukemia 1 (Mcl‐1). The model was calibrated using in vitro viability data for the MV‐4‐11 acute myeloid leukemia cell line under continuous incubation for 72 hours at concentrations of 0.03–30 μM. Using a virtual screen, we identified two schedules as having significantly different predicted efficacy and showed experimentally that a “short” schedule (treating cells for 6 of 24 hours) is significantly better able to maintain the rate of cell kill during treatment than a “long” schedule (18 of 24 hours). This work suggests that resistance can be driven by heterogeneity in protein expression of Mcl‐1 alone without requiring mutation or resistant subclones and demonstrates the utility of mathematical models in efficiently identifying regimens for experimental exploration.

MAPK-targeted therapies fail to achieve complete remission. Here, the authors show that anti-apoptosis resistance is acquired in these targeted therapies through the mRNA destabilization of NOXA which leads to dependence on MCL-1, and that sequential combination of MCL-1 inhibition with targeted therapies overcomes this resistance.

High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.